4-[[9-Chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-D][2]benzazepin-2-yl]amino] -Preparation of 2-methoxybenzoic acid_Kain Industrial Additive

Background and overview^[1][2]

Lung cancer is mainly divided into two categories based on histopathology: small cell lung cancer and non-small cell lung cancer. Non-small cell lung cancer includes squamous cell carcinoma (squamous cell carcinoma), adenocarcinoma, large cell lung cancer, and small cell lung cancer. Compared with other cancer cells, they grow and divide quickly and spread and metastasize relatively early. Lung cancer seriously threatens human health. Many studies in my country have shown that the incidence and mortality of lung cancer are increasing. The estimated number of new cancer cases and deaths in China in 2015 were 733/100,000 and 610/100,000 respectively. The incidence and mortality of lung cancer ranked first among malignant tumors reported by Li Huizhang. Alisertib (codename MLN8237) is a multi-target small molecule compound jointly developed by Millennium and Takeda. Since this drug has not yet been officially launched in my country and does not have a standard Chinese translation, it is transliterated here as “alisetide”. Alisertib is an Aurora A kinase, cell cycle and mitosis inhibitor. Scientific research shows that alicetide does not have the huge side effects of conventional chemotherapy drugs and is a milder anti-cancer drug. That’s because the compound specifically targets a key enzyme, avoiding damage to healthy cells in the bone marrow and blood, and may be more effective at lower doses than drugs tested in previous studies. Phase III clinical studies evaluating alicetide in T-cell lymphoma have been launched in the United States and other regions. Alisertib, chemical name is 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-D][2]benzene Azazepin-2-yl]amino]-2-methoxybenzoic acid.

Clinical research^[3]

Alicetide: Mollaoglu et al. studied that genomic amplification of MYC family genes is prevalent in human small cell lung cancer, and MYC is elevated in a genetically engineered small cell lung cancer model lacking Rb1 and TP53 in mouse lungs. Expression can easily cause lung cancer metastasis. Aliseti is an oral Aurora kinase A inhibitor. In a multinational clinical phase II study, it was found that the overall response rate and disease control rate were 21% and 45% respectively. The disease progression time was only 2.6 months, and 53% Patients experienced grade 3 to 4 adverse drug reactions, including neutropenia (37%), anemia (12%), leukopenia (12%), and thrombocytopenia (8%). Current targeted drug research in non-small cell lung cancer focuses on epidermal growth factor receptor (EGFR) inhibitors, patients with ALK rearrangements, and patients without EGFR/ALK abnormalities or whose mutation status is unknown. EGFR mutations have been found in approximately 10% to 15% of Caucasian lung adenocarcinoma patients, most of whom are nonsmokers. In Asians, the frequency of EGFR mutations is three times higher. The most common EGFR mutations are exon 19 deletion (del19) and exon 21 L858R substitution (45%~82% and 30%, respectively), which are usually Called sensitizing mutations because they confer sensitivity to tyrosine kinase inhibitors (TKIS).

Preparation ^[1-2]

Method 1: Using 4-amino:-2-methoxybenzoate as raw material, the intermediate 4-guanidine-2-methoxybenzoate hydrochloride (VI) is obtained by reacting with aminonitrile ; Taking 1-(2-amino-5-chlorophenyl)-1-(2,6-difluorophenyl)methanone as raw material, the intermediate 1-( is prepared through diazotization, halogenation and etherification 2-iodo-5-chlorophenyl)-1-(2-fluoro-6-methoxyphenyl)methanone (VII); intermediate (VII) is obtained by Heck alkylation reaction and cyclization reaction. (E)-8-Chloro-1-(2-fluoro-6-methoxyphenyl)-3H-benzo[C]azepine-5-(4H)-one (VIII), intermediate (VIII) ) is condensed with DMF-DMA to obtain (1E, 4E)-8-chloro-4-[(dimethylamino)methylene]-1-(2-fluoro-6-methoxyphenyl)-3H-benzene And [C] azepine-5-(4H)-one (IX), intermediate (IX) and intermediate (VI) are condensed to obtain alicetide (I).

Method 2: Alisertib, 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-D] Preparation of [2]benzazepine-2-yl]amino]-2-methoxybenzoic acid, I): Preparation method:

The preparation method includes the following steps: 3-[(2-fluoro-6-methoxy)phenyl]-5-chlorophthalide (II) and acetonitrile undergo an addition reaction to generate intermediate 1,3-bis Hydrogen-1-hydroxy-3-[(2-fluoro-6-methoxy)phenyl]-5-chloro-isobenzofuran-1-acetonitrile (III); intermediate (III) and N, N- Dimethylformamide dimethyl acetal (DMF-DMA) undergoes a condensation reaction to obtain the intermediate 3-{[1-(4-chlorophenyl)-1′-(2-fluoro-6-methoxyphenyl) )methanol]-2-yl}-2-[2-(dimethylamino)methylene]-3-oxapropionitrile (IV); intermediate (IV) and 4-guanidine-2-methoxybenzene The cyclization reaction of formate hydrochloride (VI) produces the intermediate 4-{[4-[1-(4-chlorophenyl)-1′-(2-fluoro-6-methoxyphenyl)methanol] -5-nitrilepyrimidin-2-yl]amino}-2-methoxybenzoic acid (V); the intermediate (V) undergoes reduction reaction, oxidation reaction and cyclization reaction in sequence to obtain alicetide (I).

Method 3: Alisertib, 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-D] Preparation method of [2]benzazepine-2-yl]amino]-2-methoxybenzoic acid, I):

The preparation method includes the following steps: (1E, 4E)-8-chloro-4-[(dimethylamino)methylene]-1-(2-fluoro-6-methoxyphenyl)- The condensation cyclization reaction between 3H-benzo[C]azepine-5-(4H)-one (II) and guanidine hydrochloride produces 2-amino-9-chloro-7-(2-fluoro-6-methoxy Phenyl)-5H-pyrimido[5,4-D][2]benzazepine(III), 2-amino-9-chloro-7-(2-fluoro-6-methoxyphenyl) Arisetide (I) was prepared by substitution reaction between -5H-pyrimido[5,4-D][2]benzazepine (III) and 4-halogen-2-methoxybenzoic acid (IV). .

Main reference materials

[1] CN201310316251.6 ���Preparation method of Risetide

[2] CN201310316151.3 Preparation method of alicetide

[3] Yang Z, Lin C. Present Situation and Progress of Lung Cancer Therapy[J]. 2018.